LONG EXERCISE TRAINING IMPROVES HEART FUNCTION IN AGED RATS BY NO-DEPENDENT DECREASE IN MITOCHONDRIAL PORE SENSITIVITY TO CALCIUM
S.V. Chorna, N.A. Strutynska, O.M. Semenykhina, S.O. Talanov, V.E. Dosenko, A.V. Kotsuruba, G.L. Vavilova, V.F. Sagach
Bogomoletz Institute of physiology NAS of Ukraine, Kyiv, Ukraine
The effect of long exercise training on the indexes of the
functional state isolated by Lanhendorf heart of old rats
during ischemia-reperfusion, the sensitivity of calciuminduced
mitochondrial permeability transition pore (MPTP)
opening and the role of NO-dependent mechanisms of poreformation
regulatory were investigated. Thus, reperfusion
injury of the heart contractile function and its myocardial
oxygen metabolism were less pronounced in old rats adapted
to exercise long training pointing for its positive effect. It is
shown a decreased sensitivity of MPTP to its inductor Ca2+ in
the heart of old trained rats due to an increase by 1.5-2 orders
in threshold Ca2+ concentration, which induces swelling of
organelles. At the same time, in heart mitochondria of trained
adult rats we observed almost doubled activity of constitutive
NO-synthase (cNOS) compared with control (6,02 Ѓ} 0,08 and
3,64 Ѓ} 0,27 pmol / min * mg protein, respectively (P.0,05 ))
and a slight increase in the activity of inducible NO-synthase
(iNOS). Regulation of pore formation in older animals trained
was performed by a significant decreased iNOS activity
compared with control aged rats (12,29 Ѓ} 3,11 and 9,25 Ѓ}
1,24 pmol/min*mg protein, respectively (P.0,05)) on the
background slight increased in cNOS activity. We hypothesized
that a decrease in sensitivity of the MPTP-opening occurred
due to an increased production of NO pointing to its role as
an inhibitor of pore formation during exercise. It has been
shown to increase the sensitivity of MPTP to Ca2+ in the
heart under the conditions of reduce the NO production by a
single injection of NO syhnthase inhibitor N(omega)-nitro-
L-arginine methyl ester (L-NAME) in dose of 10 mg/kg to
trained animals of all ages. Using real-time polymerase chain
reaction we showed that the gene expression of eNOS in the
heart was significantly greater than that of nNOS and iNOS.
Thus, in the heart of adult trained rats the expression of mRNA
nNOS were increased 5 times, mRNA iNOS - 24 times (P
<0,05), and the gene expression of eNOS decreased 3.5 times
compared with untrained rats. In the heart of old trained rats
the expression of nNOS mRNA decreased 4 times (P<0,05)
and iNOS mRNA - 2 times compared with the old untrained
animals. In heart of old trained rats we observed a workout
recovery of eNOS mRNA expression to the values of control
adult animals. Taken together, our data suggest that a longterm
exercise training improves functional state of the heart
during aging and increases the resistance of body to oxidative
stress under reperfusion injury due to a decreased sensitivity of
MPTP to Ca2+ and increased activity of mitochondrial cNOS.
exercise training, heart, ischemia-reperfusion,mitochondrial permeability transition pore, nitric oxide, geneexpression, aging rats.
- Hull SS, Vanoli E, Adamson PB Verrier RL, Foreman RD, Schwartz PJ. Exercise training confers anticipatory protection from sudden death during acute myocardial ischemia. Circulation. 1994; 89: 548-552.
- Powers, SK, Demirel HA, Vincent HK Coombes JS, Naito H, Hamilton KL, Shanely AR, Jessup J. Exercise training improves myocardial tolerance to in vivo ischemia- reperfusion in the rat. Am J Physiol. 1998; 275: 1468-1477.
- Campos JC, Gomes K MS, Ferreira JCB. Impact of exercise training on redox signaling in cardiovascular diseases. Food and Chemic Toxicol. 2013; 62: 107–119.
- Williams MA, Fleg JL, Ades PA, Chaitman BR, Miller NH, Mohiuddin SM, Ockene IS, Taylor CB, Wenger NK. Secondary prevention of coronary heart disease inthe elderly (with emphasis on patients ? 75 years of age): An American Heart Association Scientific Statementfrom the Council on Clinical Cardiology Subcommittee on Exercise, Cardiac Rehabilitation, and Prevention.Circulatio. 2002; 105(14): 1735-1743.
- Lennon SL, Quindry JC, French JP, Kim S, Mehta JL, Powers SK Exercise and myocardial tolerance to ischaemiareperfusion. Acta Physiol Scand. 2004; 182: 161-169
- Demirel HA, Powers SK, Zergeroglu MA, Shanely R A, Hamilton K, Coombes J, Naito H. Short-term exercise improves myocardial tolerance to in vivo ischemia-reperfusion in the rat. J Appl Physiol. 2001; 91: 2205–2212.
- Ciminelli M, Ascah A, Bourduas K, Burelle Y. Short term training attenuates opening of the mitochondrial permeability transition pore without affecting myocardial function following ischemia-reperfusion. Mol Cell Biochem. 2006; 291: 39-47.
- Bernardi P, Di Lisa F The mitochondrial permeabilitytransition pore: Molecular nature and role as a target in cardioprotection. J Mol and Cell Cardiol.
- Brookes PS. Mitochondrial nitric oxide synthase. Mitochondrion.2004; 3: 187–204.
- Lacza Z, Pankotai E, Busija DW. Mitochondrial nitric oxide synthase: current concepts and controversies. Front Biosci. 2009; 14: 4436-4443.
- Li H, Forstermann U. Nitric oxide in the pathogenesis of vascular disease. J Pathol. 2000; 90: 244-254
- Chorna SV, Talanov SO, Strutynska NA. Vavilova G.L., Kotsuruba A.V., Gaidai N.M., Sagach V.F. The functional state the rat heart during ischemia-reperfusion, the sensitivity of calcium-induced mitochondrial permeability transition pore opening and the uncoupling protein 3 expression following long exercise training. Fiziol Zh.2010; 56 (2): 13-21.
- Sagach VF, Vavilova GL, Rudyk OV, Strutynska NA. Release of unidentified substances of mitochondrial origin--evidence of mitochondrial permeability transition pore opening in the heart mitochondria of rats. Fiziol Zh.2003; 49 (5): 3-12.
- Sagach VF, Rudyk OV, Vavilova GL Kotsiuruba AV, Tkachenko JuP. Melatonin recovers ischemic tolerance and decreases the sensitivity of mitochondrial permeability transition pore opening in the heart of aging rats. Fiziol Zh. 2006; 52 (3): 3-14.